Estimating multilocus linkage disequilibria.
The state of a diploid population segregating for two alleles at each of n loci is described by 22n genotype frequencies, or equivalently, by allele frequencies and by multilocus moments or cumulants of various orders. These measures of linkage disequilibrium cannot usually be determined, both because one cannot tell whether a gene came from the maternal or paternal gamete, and because such a large number of parameters cannot be estimated even from large samples. Simplifying assumptions must therefore be made. This paper sets out methods for estimating multilocus genotype frequencies which are appropriate for unlinked neutral loci, and for populations that are ultimately derived by mixing of two source populations. In such a hybrid population, all multilocus associations depend primarily on the number of loci involved that derive from the maternal genome, and the number derived from the paternal genome. Allele frequencies may differ across loci, and the contribution of each locus to multilocus associations may be scaled by the difference in allele frequency between source populations for that locus (deltap </= 1). For example, the cumulant describing the association between genes i, j, k from the maternal genome, and genes i, l from the paternal genome is kappai,j,k,i*l*, = deltapi2 deltapj deltapk deltapl kappa3,2. The state of the population is described by n allele frequencies; n divergences, deltap; and by a symmetric matrix of cumulants, kappaJ,K (J=0,ellipsis, n, K=0, ellipsis, n). Expressions for these cumulants under short- and long-range migration are given. Two methods for estimating the cumulants are described: a simple method based on multivariate moments, and a maximum likelihood procedure, which uses the Metropolis algorithm. Both methods perform well when tested against simulations with two or four loci.


Immunophilins and thrombotic disorders.
The immunophilin family includes a large group of proteins with peptidyl prolyl-isomerase activity (PPI-ase). Immunophilins chaperone activity has been documented to be crucial for the correct folding and activation of many proteins. Thus, they have been subjected of intense investigation since they were firstly described in the last decades of the past century. Many of these studies have been focused on leukocyte constitutively expressed immunophilins, due to their relevance in the correct folding, and subsequently, sensitization and activation of the glycoprotein receptor (RGBs) of lymphocyte T CD4+ and Treg, hence regulating immunological responses against pathogen insults. Several clinical trials have been completed in the last decade reporting that administration of immunophilin-binding drugs, derived from macrolide lactones, like cyclosporine A (CsA) and tacrolimus (FK506), induced successful results in preventing organ rejection. By contrast, the expression of immunophilins and their physiological function remain poorly investigated in others cell types, such as platelets, where a reduced number of studies presenting evidences of immunophilins expression and their physiological contribution have been published, despite a number of clinical trials have noticed side effects of these drugs in thrombosis and platelet count, thus suggesting a possible regulatory function of immunophilins in human platelets, which is reviewed here.


Distribution of heme oxygenase and effects of exogenous carbon monoxide in canine jejunum.
Carbon monoxide (CO) has been postulated to be a messenger in the gastrointestinal tract. The aims of this study were to determine the distribution of heme oxygenase (HO), the source for endogenous CO in the canine jejunum, and to determine the effects of CO on jejunal circular smooth muscle cells. HO-2 isoform was present in a population of myenteric and submucosal neuronal cell bodies, in nerve fibers innervating the muscle layers, and in smooth muscle cells. HO-1 isozyme was not detected in the canine jejunum. Exogenous CO increased whole cell current by 285 +/- 86%, hyperpolarized the membrane potential by 8.5 +/- 2.9 mV, and increased guanosine 3',5'-cyclic monophosphate (cGMP) levels in smooth muscle cells. 8-Bromo-cGMP also increased the whole cell current. The data suggest that endogenous activity of HO-2 may be a source of CO in the canine jejunum and that exogenously applied CO can modulate intestinal smooth muscle electrical activity. It is therefore reasonable to suggest a role for endogenously produced CO as a messenger in the canine jejunum.


Metabolic profiling of a polyphenolic-rich fraction of Coccinia grandis leaves using LC-ESI-MS/MS and in vivo validation of its antimicrobial and wound healing activities.
A polyphenolic-rich fraction (CG50) was obtained from the methanol extract of Coccinia grandis leaves by chromatographic fractionation over a Diaion column using 50% aqueous methanol. LC-ESI-MS/MS analysis of CG50 showed the presence of six flavonoids, namely quercetin-hexoside deoxyhexoside (rutin), quercetin-hexoside deoxyhexoside (quercetin-3-O-neohesperidoside), kaempferol-hexoside deoxyhexoside (kaempferol-3-O-rutinoside), kaempferol-hexoside deoxyhexoside (kaempferol-3-O-neohesperidoside), kaempferol-3-O-glucoside, and kaempferol-hexoside in addition to the presence of two secoiridoids which are oleuropein and ligstroside. CG50 hydrogel showed a pronounced inhibition of the bacterial growth in wounds infected by Bacillus cereus in rats comparable to those treated with hydrogel base only showing 85.08 and 16.50% inhibition for the bacterial growth for the CG50 hydrogel and hydrogel base, respectively. The antimicrobial activity of CG50 hydrogel was close to that of fucidin during all days of treatment. Rats treated with CG50 hydrogel showed remarkable healing ability of the wound compared to other groups and approaching that of fucidin. This was clearly manifested by the clear formation of scars with obvious reduction in the wound size together with the appearance and re-growth of hair. This was further confirmed by the histopathological study of skin tissues as well as by the evaluation of the percentages of collagen fiber deposition. CG50 hydrogel showed 18.71% collagen fiber deposition comparable to the untreated group that showed 6.84% collagen fiber deposition and approaches that of the fucidin group. It was concluded that Coccinia grandis could be used as a natural wound healing agent that further consolidated its traditional use as a wound dressing.


Luteinizing hormone regulates the phosphorylation and localization of the mitochondrial effector dynamin-related protein-1 (DRP1) and steroidogenesis in the bovine corpus luteum.
The corpus luteum is an endocrine gland that synthesizes and secretes progesterone. Luteinizing hormone (LH) activates protein kinase A (PKA) signaling in luteal cells, increasing delivery of substrate to mitochondria for progesterone production. Mitochondria maintain a highly regulated equilibrium between fusion and fission in order to sustain biological function. Dynamin-related protein 1 (DRP1), is a key mediator of mitochondrial fission. The mechanism by which DRP1 is regulated in the ovary is largely unknown. We hypothesize that LH via PKA differentially regulates the phosphorylation of DRP1 on Ser616 and Ser637 in bovine luteal cells. In primary cultures of steroidogenic small luteal cells (SLCs), LH, and forskolin stimulated phosphorylation of DRP1 (Ser 637), and inhibited phosphorylation of DRP1 (Ser 616). Overexpression of a PKA inhibitor blocked the effects of LH and forskolin on DRP1 phosphorylation. In addition, LH decreased the association of DRP1 with the mitochondria. Genetic knockdown of the DRP1 mitochondria receptor, and a small molecule inhibitor of DRP1 increased basal and LH-induced progesterone production. Studies with a general Dynamin inhibitor and siRNA knockdown of DRP1 showed that DRP1 is required for optimal LH-induced progesterone biosynthesis. Taken together, the findings place DRP1 as an important target downstream of PKA in steroidogenic luteal cells.


[Kinematics of metachronous walking. I. Configurations].
?The notion of configuration of legs' spatial distribution is presented. The relationships between the legs' spatial distribution and the features of meachronal activity in the ipsilateral legs row of some less than abstract greater than animal's locomatory system were investigated on the basis of theoretical analysis of different configurations. Some hypotheses about the control of legs' metachronal activity are proposed.


Reversal of age-related increase in brain protein oxidation, decrease in enzyme activity, and loss in temporal and spatial memory by chronic administration of the spin-trapping compound N-tert-butyl-alpha-phenylnitrone.
Oxygen free radicals and oxidative events have been implicated as playing a role in bringing about the changes in cellular function that occur during aging. Brain readily undergoes oxidative damage, so it is important to determine if aging-induced changes in brain may be associated with oxidative events. Previously we demonstrated that brain damage caused by an ischemia/reperfusion insult involved oxidative events. In addition, pretreatment with the spin-trapping compound N-tert-butyl-alpha-phenylnitrone (PBN) diminished the increase in oxidized protein and the loss of glutamine synthetase (GS) activity that accompanied ischemia/reperfusion injury in brain. We report here that aged gerbils had a significantly higher level of oxidized protein as assessed by carbonyl residues and decreased GS and neutral protease activities as compared to young adult gerbils. We also found that chronic treatment with the spin-trapping compound PBN caused a decrease in the level of oxidized protein and an increase in both GS and neutral protease activity in aged Mongolian gerbil brain. In contrast to aged gerbils, PBN treatment of young adult gerbils had no significant effect on brain oxidized protein content or GS activity. Male gerbils, young adults (3 months of age) and retired breeders (15-18 months of age), were treated with PBN for 14 days with twice daily dosages of 32 mg/kg. If PBN administration was ceased after 2 weeks, the significantly decreased level of oxidized protein and increased GS and neutral protease activities in old gerbils changed in a monotonic fashion back to the levels observed in aged gerbils prior to PBN administration. We also report that old gerbils make more errors than young animals and that older gerbils treated with PBN made fewer errors in a radial arm maze test for temporal and spatial memory than the untreated aged controls. These data can be interpreted to indicate that oxidation of cellular proteins may be a critical determinant of brain function. Moreover, it also implies that there is an age-related increase in vulnerability of tissue to oxidation that can be modified by free radical trapping compounds.


A Clinico-analytical Study on Seed of Wrightia antidysenterica Linn. as a Therapeutic Emetic Agent (Vamaka Yoga) in the Management of Psoriasis.
Wrightia antidysenterica Linn. (WA) is male variety Kutaja stated to be potent therapeutic emetic agent in skin disorders. Expulsion of doshas through oral route is termed as Vamana Karma (VK) (therapeutic emesis). However, so far, its utility for Vamana is not explored in detail, therefore there is a need to revalidate the utility of WA for Vamana. Hence, the above study was conducted to ascertain the efficacy as a therapeutic emetic agent (vamaka yoga) in the management of psoriasis along with quality control and standardization of this herb. The drug was standardized as per analytical procedures in Pharmacopeias. Thirty patients of psoriasis fulfilling inclusion criteria were taken for the study and Vamana with WA was conducted. Criteria were prepared to assess the signs and Symptoms of psoriasis. VK was assessed using the classical Lakshanas (features) such as Anthiki shudhi (Ending symptoms of emesis), Vaigiki shudhi (features of vomiting bouts), Maniki shudhi (Quantitative and qualitative purification), complications. VK with WA showed significant relief in parameters of psoriasis such as scaling, itching, candle grease sign (P < 0.001), and psoriasis area and severity index score (P = 0.001). In VK with WA, mean number of Vegas (vomiting bouts) was 6.91. 66% patients showing quantitative purification between 301 and 600 ml. 73.33% showed all Symptoms of purification. 73.33% patients showed Kaphanta vamana (Moderate expulsion of desire humor). In the level of biopurification, 66.66% patients showed moderated purification. No complication was noted with moderate drug palatability. Pharmacopeial analytical study showed its standardized values for testing the drug used for the study. It is proved as potent therapeutic emetic agent with no complication showed its clinical benefits over skin disorder like psoriasis. Seeds of Wrightia antidysenterica (WA) Linn. free from any foreign matter were selected for the study. Loss on drying revealed 6.535% moisture content; total ash indicating of total inorganic content was found to be 5.12%; acid insoluble ash is the acid insoluble part of total ash, mainly silica, WA showed 0.393% acid insoluble ash; ethanol and water soluble extractive is indicative of percentage active constituents were found to be 25.66 and 20.854%, respectively. High-performance thin layer chromatography fingerprinting profiles of WA under 254 nm showed the presence of 7 spots (all in green) at Rf values ranging from 0.21 to 0.88. Under 366 nm there were 4 prominent spots (all in fluorescent) at Rf 0.49 to 0.82 and, when scanned under white light 620 nm following derivatization with vanillin sulfuric acid 6 spots (in different colors) were evident at Rf 0.28 to 0.58. Among these spot with Rf of 0.58 was common when visualized under all the three methods. Rf values by densitometric scan of WA showed 12 peaks at 254 nm and 5 peaks at 366 nm. However, in clinical trial, it was found to be a potent emetic agent without any complication. Abbreviations Used: WA: Wrightia antidysenterica; Linn.; VK: Vamana karma; BT: Before treatment; FP: Freidman's P value; CHS: Chi-square value; NR: Negative ranks; PR: Positive ranks; N: Sample number, AS: Austipz sign; CG: Candle grease test; SSL: Samyak Snigdha Lakshana.


Constrained binary classification using ensemble learning: an application to cost-efficient targeted PrEP strategies.
Binary classification problems are ubiquitous in health and social sciences. In many cases, one wishes to balance two competing optimality considerations for a binary classifier. For instance, in resource-limited settings, an human immunodeficiency virus prevention program based on offering pre-exposure prophylaxis (PrEP) to select high-risk individuals must balance the sensitivity of the binary classifier in detecting future seroconverters (and hence offering them PrEP regimens) with the total number of PrEP regimens that is financially and logistically feasible for the program. In this article, we consider a general class of constrained binary classification problems wherein the objective function and the constraint are both monotonic with respect to a threshold. These include the minimization of the rate of positive predictions subject to a minimum sensitivity, the maximization of sensitivity subject to a maximum rate of positive predictions, and the Neyman-Pearson paradigm, which minimizes the type II error subject to an upper bound on the type I error. We propose an ensemble approach to these binary classification problems based on the Super Learner methodology. This approach linearly combines a user-supplied library of scoring algorithms, with combination weights and a discriminating threshold chosen to minimize the constrained optimality criterion. We then illustrate the application of the proposed classifier to develop an individualized PrEP targeting strategy in a resource-limited setting, with the goal of minimizing the number of PrEP offerings while achieving a minimum required sensitivity. This proof of concept data analysis uses baseline data from the ongoing Sustainable East Africa Research in Community Health study. Copyright © 2017 John Wiley & Sons, Ltd.


Watermarking sexually reproducing diploid organisms.
DNA watermarks are used for hiding messages or for authenticating genetically modified organisms. Recently, we presented an algorithm called DNA-Crypt for generating DNA-based watermarks that can be integrated into the genome by using the characteristics of the degenerative genetic code. DNA-Crypt generates the watermark by replacing single bases and thus creating synonymous codons that encrypt the hidden information. Mutations within the integrated DNA sequence can be corrected using several mutation correction codes, to keep the hidden information intact. This method has successfully been tested in asexually replicating organisms like bacteria or yeast, where the watermark is duplicated with every cell division. It has been shown that DNA watermarks produced by DNA-Crypt do not influence the transcription or translation of a protein. In sexually reproducing diploid organisms, additional problems can occur, e.g. recombination events can destroy hidden information. Using population predictions as well as statistical analyses we identified a coupled Y-chromosomal/mitochondrial DNA watermarking procedure as the most appropriate for diploid organisms. We developed a mitochondria adapted version of DNA-Crypt, which is called Project Mito that can be used in combination with the original program. http://www.uni-muenster.de/Biologie.NeuroVer/Tumorbiologie/DNA-Crypt/index.html


Do variable compensatory mechanisms explain the polymorphism of the dependence phenotype in the Asobara tabida-wolbachia association?
Wolbachia are symbiotic intracellular bacteria, which are classified as reproductive parasites. Although generally facultative, Wolbachia is necessary for Asobara tabida (Hymenoptera), because aposymbiotic females do not produce any offspring. Interestingly, the ovarian phenotype of aposymbiotic females is variable: some females do not produce any eggs, whereas others do produce some eggs, but these are aborted. Here, we show that the ovarian phenotype of aposymbiotic females is highly polymorphic within populations, although dependence remains complete in both cases. We also identified some lines in which aposymbiotic females were able to produce a very few viable offspring, further extending the range of variation observed. These results suggest that various factors actively maintain polymorphism. We demonstrated that Wolbachia is necessary to trigger oogenetic processes, but that the ovarian phenotype was determined by the host only. Phenotypic variation was also correlated with the differential expression of genes controlling iron homeostasis and oxidative stress, which are potentially involved in the evolution of dependence. This suggests that variation in the ovarian phenotype could reflect selection for different levels of compensatory mechanisms in response to Wolbachia infection, and that polymorphism is maintained through selection on different antagonist traits influenced by oxidative stress.


Dynamic high resolution positron emission imaging of rats.
The performance criteria for a dedicated rat positron emission tomography has been investigated. A survey of researchers indicated that 3 mm image spatial resolution and 2 second dynamic imaging capabilities were desirable characteristics for a dedicated system. Monte Carlo computer simulations were used to evaluate potential PET designs. The conclusion from the simulations were twofold: 1) unlike human imaging where both sensitivity and spatial resolution limitations significantly effect the quantitative imaging performance of a tomograph, the imaging performance of a dedicated rat tomography is almost solely based upon its spatial resolution limitations and 2) desirable performance could be obtained using a novel multi-layered detector system. Computer simulations were run to evaluate economical modular detector implementations. Two optimal dedicated rat PET designs were found, and prototype multilayered detector module is currently being constructed.


Finger Pad Topography beyond Fingerprints: Understanding the Heterogeneity Effect of Finger Topography for Human-Machine Interface Modeling.
With the rapid development of haptic devices, there is an increasing demand to understand finger pad topography under different conditions, especially for investigation of the human-machine interface in surface haptic devices. An accurate description of finger pad topography across scales is essential for the study of the interfaces and could be used to predict the real area of contact and friction force, both of which correlate closely with human tactile perception. However, there has been limited work reporting the heterogeneous topography of finger pads across scales. In this work, we propose a detailed heterogeneous finger topography model based on the surface roughness power spectrum. The analysis showed a significant difference between the topography on ridges and valleys of the fingerprint and that the real contact area estimation could be different by a factor of 3. In addition, a spatial-spectral analysis method is developed to effectively compare topography response to different condition changes. This paper provides insights into finger topography for advanced human-machine interaction interfaces.


Receptors with low affinity for neurosteroids and GABA contribute to tonic inhibition of granule cells in epileptic animals.
Neurosteroid sensitivity of GABA(A) receptor mediated inhibition of the hippocampal dentate granule cells (DGCs) is reduced in animal models of temporal lobe epilepsy. However, the properties and subunit composition of GABA(A) receptors mediating tonic inhibition in DGCs of epileptic animals have not been described. In the DGCs of epileptic animals, allopregnanolone and L-655708 sensitivity of holding current was diminished and δ subunit was retained in the endoplasmic reticulum and its surface expression was decreased the in the hippocampus. Ro15-4513 and lanthanum had distinct effects on holding current recorded from DGCs of control and epileptic animals suggesting that the pharmacological properties of GABA(A) receptors maintaining tonic inhibition in DGCs of epileptic animals were similar to those containing the α4βxγ2 subunits. Furthermore, surface expression of the α4 subunit increased and a larger fraction of the subunit co-immunoprecipitated with theγ2 subunit in hippocampi of epileptic animals. Together, these studies revealed that functional α4βxδ and α5βxγ2 receptors were reduced in the hippocampi of epileptic animals and that novel α4bxγ2 receptors contributed to the maintenance of tonic inhibition. The presence of α4βxγ2 receptors resulted in low GABA affinity and neurosteroid sensitivity of tonic currents in the DGCs of epileptic animals that could potentially increase seizure vulnerability. These receptors may represent a novel therapeutic target for anticonvulsant drugs without sedative actions.


Hate speech detection: Challenges and solutions.
As online content continues to grow, so does the spread of hate speech. We identify and examine challenges faced by online automatic approaches for hate speech detection in text. Among these difficulties are subtleties in language, differing definitions on what constitutes hate speech, and limitations of data availability for training and testing of these systems. Furthermore, many recent approaches suffer from an interpretability problem-that is, it can be difficult to understand why the systems make the decisions that they do. We propose a multi-view SVM approach that achieves near state-of-the-art performance, while being simpler and producing more easily interpretable decisions than neural methods. We also discuss both technical and practical challenges that remain for this task.


Quadrupedal coordination of bipedal gait: implications for movement disorders.
During recent years, evidence has come up that bipedal locomotion is based on a quadrupedal limb coordination. A task-dependent neuronal coupling of upper and lower limbs allows one to involve the arms during gait but to uncouple this connection during voluntarily guided arm/hand movements. Hence, despite the evolution of a strong cortico-spinal control of hand/arm movements in humans, a quadrupedal limb coordination persists during locomotion. This has consequences for the limb coordination in movement disorders such as in Parkinson's disease (PD) and after stroke. In patients suffering PD, the quadrupedal coordination of gait is basically preserved. The activation of upper limb muscles during locomotion is strong, similar as in age-matched healthy subjects although arm swing is reduced. This suggests a contribution of biomechanical constraints to immobility. In post-stroke subjects a close interactions between unaffected and affected sides with an impaired processing of afferent input takes place. An afferent volley applied to a leg nerve of the unaffected leg leads to a normal reflex activation of proximal arm muscles of both sides. In contrast, when the nerve of the affected leg was stimulated, neither on the affected nor in the unaffected arm muscles EMG responses appear. Muscle activation on the affected arm becomes normalized by influences of the unaffected side during locomotion. These observations have consequences for the rehabilitation of patients suffering movement disorders.


Bacterial collagenase. Proposed adjunct to vitrectomy with membranectomy.
Clostridiopeptidase A digested preretinal cicatricial tissue without causing morphological alteration of normal retina during a 30-minute incubation in the rabbit. Light and transmission electron microscopy were used to determine effects on the inner limiting membrane and retinal ganglion and Müller's cells and to evaluate enzyme digestion of preretinal scarring. Removal of the injected collangenase by vitrectomy resulted in normal electroretinograms and retinal morphology 48 hours postoperatively. If the enzyme was left in the eye for 24 hours, lens opacities, partial erosion of the inner limiting membrane, and extensive hemorrhage resulted. The specificity of action of the collagenase is due to the high degree of purity of the enzyme used and a substantial biochemical difference between scar collagen and basement membrane collagen. The injection of purified collagenase capable of digesting vitreal scar tissue while leaving the retina undamaged could represent a new approach to vitrectomy, specifically to facilitate certain cases of membranectomy.


Protective efficacy of influenza group 2 hemagglutinin stem-fragment immunogen vaccines.
The stem of the influenza A virus hemagglutinin (HA) is highly conserved and represents an attractive target for a universal influenza vaccine. The 18 HA subtypes of influenza A are phylogenetically divided into two groups, and while protection with group 1 HA stem vaccines has been demonstrated in animal models, studies on group 2 stem vaccines are limited. Thus, we engineered group 2 HA stem-immunogen (SI) vaccines targeting the epitope for the broadly neutralizing monoclonal antibody CR9114 and evaluated vaccine efficacy in mice and ferrets. Immunization induced antibodies that bound to recombinant HA protein and viral particles, and competed with CR9114 for binding to the HA stem. Mice vaccinated with H3 and H7-SI were protected from lethal homologous challenge with X-79 (H3N2) or A/Anhui/1/2013 (H7N9), and displayed moderate heterologous protection. In ferrets, H7-SI vaccination did not significantly reduce weight loss or nasal wash titers after robust 107 TCID50 H7N9 virus challenge. Epitope mapping revealed ferrets developed lower titers of antibodies that bound a narrow range of HA stem epitopes compared to mice, and this likely explains the lower efficacy in ferrets. Collectively, these findings indicate that while group 2 SI vaccines show promise, their immunogenicity and efficacy are reduced in larger outbred species, and will have to be enhanced for successful translation to a universal vaccine.


A potential role of triple therapy for asthma patients.
Introduction: The use of LAMAs in asthma is now supported by pharmacological and clinical evidence, whereas the effectiveness of therapy with ICS/LABA/LAMA fixed dose combinations in patients with asthma still remains to be determined. Areas covered: The pharmacological rationale that explains why it is possible to use triple therapy in asthma and the results of clinical studies that have explored the effects of this therapy in asthmatics is critically examined. A systematic search was conducted on 10 August 2019, and included six electronic databases: EMBASE, MEDLINE, Scopus, The Cochrane Library, Web of Science, and Google Scholar. Expert opinion: The real role of single inhaler triple therapy in asthma will be demonstrated when the various trials that are currently ongoing or are scheduled will be completed. We believe that it is appropriate to treat with triple therapy asthmatic patients who have smoked and remain symptomatic or suffer from frequent exacerbations despite initial inhaler therapy with ICS/LABA. However, we must establish when to step up or mainly step down triple therapy especially in patients who are well controlled, and what will be the cost of these combinations in the management of asthma.


Periimplantitis.
Orodental rehabilitation through the use of implants offers very high success rates. In this paper, we describe some of the complications involved with this technique, such as periimplant disease and, within this category, periimplantitis, an inflammatory reaction in which there is a loss of the bony support of the implant accompanied by inflammation. The aetiology of the disease is conditioned by the status of the tissue surrounding the implant, implant design, degree of roughness, the poor alignment of implant components, external morphology and excessive mechanical load. The microorganisms most commonly associated with implant failure are spirochetes and mobile forms of Gram-negative anaerobes, unless the origin is the result of simple mechanical overload. Diagnosis is based on changes of colour in the gum, bleeding and probing depth of periimplant pockets, suppuration, x-ray and gradual loss of bone height around the tooth. Treatment will differ depending upon whether it is a case of mucositis or periimplantitis. Therapeutic objectives focus on correcting technical defects by means of surgery and decontamination techniques (abrasion with carbon particles, citric acid solution, topical tetracycline application and laser surgery). This study also presents a microbiological study of periimplantitis conducted by the Barcelona School of Dentistry that determined that the antibiotic therapy proven to be most efficacious in the antibiogram was the association of amoxycillin and clavulanic acid.


Experience with pulmonary resection for extensively drug-resistant tuberculosis.
Extensively drug-resistant tuberculosis is becoming a global threat. It is a relatively new phenomenon, and its optimal management remains undetermined. We report our experience in using pulmonary resection for treating patients with this disease. Records were reviewed of 54 consecutive patients undergoing a pulmonary resection for multidrug-resistant tuberculosis at Fukujuji Hospital between 2000 and 2006. These patients were identified using the definition approved by the World Health Organization Global Task Force on extensively drug-resistant tuberculosis in October 2006. Five (9%) patients (3 men and 2 women) aged 31-60 years met the definition. None of the patients was HIV-positive. Although the best available multidrug regimens were initiated, no patient could achieve sputum conversion. Adjuvant resectional surgery was considered because the patients had localized disease. Procedures performed included pneumonectomy (2) and upper lobectomy (3). There was no operative mortality or morbidity. All patients attained sputum-negative status after the operation, and they were maintained on multidrug regimens for 12-25 months postoperatively. All patients remained free from disease at the time of follow-up. Pulmonary resection under cover of state-of-the-art chemotherapy is safe and effective for patients with localized extensively drug-resistant tuberculosis.


Adaptive aromaticity in 16-valence-electron metallazapentalenes.
According to Hückel's and Baird's rules, cyclic species are generally aromatic only either in the lowest singlet state (S0) or in the lowest-lying triplet ππ* excited state (T1). Thus, species with aromaticity both in S0 and T1 states (termed as adaptive aromaticity) are particularly rare. Herein, we carry out density functional theory (DFT) calculations to examine the aromaticity of 16e metallapentalenes containing heteroatoms (N, O). Interestingly, metallazapentalenes show adaptive aromaticity whereas metalloxapentalenes display nonaromaticity in the S0 and T1 states, which is supported by structural, magnetic, and electronic indices. In addition, a series of metallazapentalenes containing strong σ- or π-donor ligands are predicted to achieve adaptive aromaticity. Our findings expand the family of adaptive aromatics significantly, inviting experimental chemists to realize more hetero-metallapentalenes with adaptive aromaticity.


Hepatitis E virus infection in hematopoietic stem cell transplant recipients: a systematic review and meta-analysis.
Although most patients with hepatitis E virus (HEV) infection are asymptomatic or have mild symptoms, its infection is generally underdiagnosed and overlooked. In immunocompromised patients, HEV infection can lead to acute liver failure and death. However, the clinical evidence of HEV infection in hematopoietic stem cell transplant (HSCT) recipients is scarce; thus, we conducted this systematic review and meta-analysis to assess the prevalence of HEV infection in this population. We searched MEDLINE, EMBASE, and the Cochrane Library databases from inception through October 2020 to identify studies that reported the prevalence of HEV infection among HSCT recipients. HEV infections were confirmed by HEV-IgG/IgM or HEV-RNA assay. A total of 1977 patients from nine studies with a follow-up time up to 40 months were included in the final analysis. The pooled prevalence of positive HEV-RNA was 3.0% (95% CI 2.3% to 4.0%). The pooled prevalence of positive HEV-IgG was 10.3% (95% CI 4.5% to 21.8%). The pooled prevalence of de novo HEV infection was 2.9% (95% CI 1.8% to 4.5%). Age and male gender were not associated with HEV-RNA or HEV-IgG positivity in the meta-regression analysis. In conclusion, the prevalence of HEV-IgG in HSCT recipients was about 10%, while the prevalence of HEV-RNA was only 3%. However, further studies that focus on the clinical outcomes in this population are warranted.


Early Results of Edge-to-Edge Alfieri Mitral Repair Via Right Mini-Thoracotomy in 68 Consecutive Patients.
: To examine early outcomes of mitral valve repair using Alfieri repair via a right mini-thoracotomy approach. : Records were examined in 68 consecutive patients undergoing Alfieri mitral repair via 6 cm right mini-thoracotomy. Most repairs were performed under cardioplegic arrest, using percutaneous femoral cannulation and direct aortic cannulation through the right first intercostal space. All patients without hypertrophic cardiomyopathy received rigid ring annuloplasty. The indications for Alfieri repair were extensive prolapse with ring size at least 30 mm. : Mean age was 56 ± 13 (range, 20-80). Mitral disease etiology was Barlow disease in 17 of 68 (25%) patients and myxomatous disease in 47 of 68 (69%). Concurrent procedures were performed in 29 of 68 (43%) patients. Median ring size was 34 mm. Despite extensive leaflet disease, 59 of 68 (87%) patients were repaired without leaflet resection. Chord pairs were inserted on the posterior leaflet in 18 of 68 (26%) patients and anterior leaflet in four patients. There were no 30-day or late deaths. Residual intraoperative mitral regurgitation was absent in 54 of 68 (79%) patients and trace in the remainder. Local echocardiography follow-up at a mean of 99 days showed median residual regurgitation to be trace. Only two patients developed moderate regurgitation. Mean mitral gradient at follow-up was 4 ± 2 mm Hg. Local follow-up showed 28 of 39 (72%) patients to be New York Heart Association class I. : An edge-to-edge Alfieri repair via mini-thoracotomy can provide excellent short-term results in selected patients with complex myxomatous mitral disease when minimizing the need for leaflet resection.


Prognostic implications of node metastatic features in OSCC: a retrospective study on 121 neck dissections.
Lymph node metastases are responsible for shorter survival in oral squamous cell carcinoma (OSCC). The aim of the present study was to assess the node metastasis frequency and survival according to the node metastasis features in 121 neck dissections (NDs) performed for OSCC, identifying evidence-based correlations and contrasts with previous literature. The retrospective study involved 121 patients affected by OSCC who had undergone modified radical ND (MRND) for therapeutic, elective reasons or after intraoperative positivity to metastasis of sentinel lymph nodes (SLN+). Node metastasis frequency and behaviour (typical vs. atypical) and their number and distribution according to pre-surgical cTNM cancer staging were considered and overall survival Kaplan-Meier curves were calculated for each group in order to compare mortality according to ND type (elective, therapeutic, after SLN+), lymph node metastatic pattern (typical or atypical), size (micrometastasis vs. macrometastasis) and number. Results showed statistically significant different overall survival according to pre-surgical staging, number of lymph nodes harvested and intent to surgery. Sentinel lymph node resulted in the sole positive node affected by metastasis in small cT1- cT2/cN0 OSCC and an ND subsequent to its positivity during intraoperative assessment may be considered an overtreatment.


Connexins form functional hemichannels in porcine ciliary epithelium.
The expression of connexins in the ciliary epithelium is consistent with gap junctions between the pigmented (PE) and nonpigmented ciliary epithelium (NPE) that form when connexon hemichannels from adjacent cells pair to form a channel. Here we present evidence that suggests undocked connexons may form functional hemichannels that permit exchange of substances between NPE and the aqueous humor. Intact porcine eyes were perfused via the ciliary artery and propidium iodide (PI) (MW 668) was added to the aqueous humor compartment as a tracer. After calcium-free solution containing PI was introduced into the aqueous humor compartment for 30 min, fluorescence microscopy revealed PI in the NPE cell layer. PI entry into the NPE was inhibited by calcium and by the connexin antagonist 18α-glycyrrhetinic acid (18-AGA). Studies also were carried out with cultured porcine NPE. Under normal conditions, little PI entered the cultured cells but calcium-free medium stimulated PI accumulation and the entry was inhibited by 18-AGA. In cells loaded with calcein (MW 622), calcium-free solution stimulated calcein exit. 18-AGA partially suppressed calcein exit in calcium-free medium. Connexin 43 and connexin 50 proteins were detected by western blot analysis in both native and cultured NPE. In the intact eye, immunolocalization studies revealed connexin 50 at the basolateral, aqueous humor-facing, margin of the NPE. In contrast, connexin 43 was observed at the junction of the PE and NPE layer and on the basolateral membrane of PE. The results point to functional hemichannels at the NPE basolateral surface. It is feasible that hemichannels might contribute to the transfer of substances between the ciliary epithelium cytoplasm and aqueous humor.


Characterization of [3H]-(2S,2'R,3'R)-2-(2',3'-dicarboxy-cyclopropyl)glycine ([3H]-DCG IV) binding to metabotropic mGlu2 receptor-transfected cell membranes.
1. The binding of the new selective group II metabotropic glutamate receptor radioligand, [3H]-(2S,2'R,3'R)-2-(2',3'-dicarboxycyclopropyl)glycine ([3H]-DCG IV), was characterized in rat mGlu2 receptor-transfected CHO cell membranes. 2. [3H]-DCG IV binding was pH-dependent, but was not sensitive to temperature. Saturation analysis showed the presence of a single binding site, with a Kd value of 160 nM and a Bmax value of 10 pmol mg(-1) protein. Binding was not sensitive to Na+-dependent glutamate uptake blockers or Cl-dependent glutamate binding inhibitors. Furthermore, up to concentrations of 1 mM, the glutamate ionotropic receptor agonists, N-methyl-D-aspartic acid (NMDA), (S)-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and kainate, did not affect [3H]-DCG IV binding. 3. Of the compounds observed to inhibit [3H]-DCG IV binding, the most potent were the recently described selective group II agonist, (+)-2-aminobicyclo-[3.1.0]hexane-2,6-dicarboxylate (LY 354740; Ki value 16 nM) and antagonist, 2-amino-2-(2-carboxycyclopropan-1-yl)-3-(dibenzopyran-4-yl) propanoic acid (LY 341495; Ki value 19 nM). As expected, for a G-protein-coupled receptor, guanosine-5'-O-(3-thiotriphosphate) (GTPgammaS) inhibited [3H]-DCG IV binding in a concentration-dependent manner, with an IC50 value of 12 nNM. 4. A highly significant correlation was observed between the potencies of compounds able to inhibit [3H]-DCG IV binding and potencies obtained for agonist activity in a GTPgamma35S binding functional assay. In addition, these studies identified a number of compounds with previously unknown activity at mGlu2 receptors, including L(+)-2-amino-3-phosphonopropionic acid (L-AP3), L(+)-2-amino-5-phosphonopentanoic acid (L-AP5), 3-((RS)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (R-CPP), N-acetyl-L-aspartyl-L-glutamic acid (NAAG) and (RS)-alpha-methylserine-O-phosphate (MSOP).


Complementary gene signature integration in multiplatform microarray experiments.
The concept of gene signature overlap has been addressed previously in a number of research papers. A common conclusion is the absence of significant overlap. In this paper, we verify the aforementioned fact, but we also assess the issue of similarities not on the gene level, but on the biology level hidden underneath a given signature. We proceed by taking into account the biological knowledge that exists among different signatures, and use it as a means of integrating them and refining their statistical significance on the datasets. In this form, by integrating biological knowledge with information stemming from data distributions, we derive a unified signature that is significantly improved over its predecessors in terms of performance and robustness. Our motive behind this approach is to assess the problem of evaluating different signatures not in a competitive but rather in a complementary manner, where one is treated as a pool of knowledge contributing to a global and unified solution.


Prevalence of cardiovascular risk factors in a population of Brazilian industry workers.
Determining the cardiovascular risk factors is essential for the primary and secondary prevention of circulatory system diseases. To obtain the prevalence of cardiovascular risk factors in a population of industry workers in Brazil. Transversal cohort study, with a sociodemographic interview to identify cardiovascular risk factors, anthropometric and blood pressure measurements and capillary blood collection for blood glucose, cholesterol and triglyceride measurement in food industry workers of both sexes. A total of 1,047 workers were assessed, with 913 (87%) of them being males, with a mean age of 36 +/- 8 years. The frequency of a sedentary lifestyle was 83% and of overweight, 63%. Systemic arterial hypertension was identified in 28% of the individuals and 45% were in the pre-hypertension range. Alterations in the blood glucose levels were identified in 49% of the participants, as well as high levels of cholesterol and triglycerides in 7% and 11% of the population, respectively. The body mass index (BMI) levels were not associated to income, but there was an inverse association with the level of schooling. Overweight and a sedentary lifestyle are the main cardiovascular risk factors in a population of industry workers.


Does multiple paternity improve fitness of the frog Crinia georgiana?
In the Australian myobatrachid frog Crinia georgiana simultaneous polyandry occurs in about half of all matings, which leads to multiple paternity, but reduced fertilization success and occasional female mortality. Multiple paternity may provide benefits to females that compensate for these costs, for example, through enhanced genetic diversity of a clutch. In nature, embryos and tadpoles of C. georgiana develop in shallow, temporary pools and may be exposed to fluctuating water levels and the risk of desiccation between rain events. Fertilization by genetically diverse sires may act as a bet hedge against these conditions. To evaluate this hypothesis, females were artificially mated with one or two males in the field and eggs and larvae reared in the laboratory under constant or fluctuating developmental conditions. Experiment 1 exposed embryos from single- and multiple-paternity clutches to conditions where eggs were completely covered during development or eggs sat in air on a moist substrate. Experiment 2 exposed freshly hatched larvae from single- and multiple-paternity clutches to constant wet conditions, where larvae were completely covered, or fluctuating wet conditions, where larvae ranged from being completely submersed to partially exposed over a 13-day cycle. We measured mean performance and best performance as alternate measures of genetic benefits. There were no effects of paternity on percent survival to hatching, time to hatching, body size at hatching, percent survival to metamorphosis, time to metamorphosis, or body size at metamorphosis. We also analyzed variance within clutches as a measure of genetic diversity. Again there were no predictable effects of multiple paternity. Polyandry does not appear to provide any genetic benefits that compensate for the high costs of polyandry in this species.


Genome-based studies indicate that the Enterococcus faecium Clade B strains belong to Enterococcus lactis species and lack of the hospital infection associated markers.
Enterococcus lactis and the heterotypic synonym Enterococcus xinjiangensis from dairy origin have recently been identified as a novel species based on 16S rRNA gene sequence analysis. Enterococcus faecium type strain NCTC 7171T was used as the reference genome for determining E. lactis and E. faecium to be separate species. However, this taxonomic classification did not consider the diverse lineages of E. faecium, and the double nature of hospital-associated (clade A) and community-associated (clade B) isolates. Here, we investigated the taxonomic relationship among isolates of E. faecium of different origins and E. lactis, using a genome-based approach. Additional to 16S rRNA gene sequence analysis, we estimated the relatedness among strains and species using phylogenomics based on the core pangenome, multilocus sequence typing, the average nucleotide identity and digital DNA-DNA hybridization. Moreover, following the available safety assessment schemes, we evaluated the virulence profile and the ampicillin resistance of E. lactis and E. faecium clade B strains. Our results confirmed the genetic and evolutionary differences between clade A and the intertwined clade B and E. lactis group. We also confirmed the absence in these strains of virulence gene markers IS16, hylEfm and esp and the lack of the PBP5 allelic profile associated with ampicillin resistance. Taken together, our findings support the reassignment of the strains of E. faecium clade B as E. lactis.


Influence of catechol-O-methyltransferase Val158Met polymorphism on startle response in the presence of high estradiol levels.
both human and animal studies have shown a somewhat complex COMT-by-sex interaction effect on brain function and dysfunction. A functional variation in the gene coding for the catechol-O-methyltransferase (COMT) enzyme, which metabolizes dopamine and noradrenaline, has been related to executive and emotional functions, and to sex dimorphism. to investigate if COMT Val158Met genotype influences startle response in pregnant women, given their physiologically elevated estradiol levels. seventy-three pregnant women were assessed in gestational week 38 for acoustic startle response, measured by electromyography of the blink reflex, during control condition, positive and negative anticipation stimuli, and pleasant and unpleasant image stimuli. A blood sample was taken for measurement of estradiol levels and genetic analysis. the results indicated a COMT Val158Met effect on startle response across all conditions (main effect of genotype, F(2,70=3.58), p=0.033), where Val/Val women displayed higher startle magnitudes than Val/Met carriers (Cohen's d=0.71). No significant difference by genotype was found in affective modulation. The findings also suggested an estrogen dose-dependent effect of COMT Val158Met on startle reflex. Among women with higher pregnancy-induced estradiol levels, Val/Val carriers had markedly higher startle response across conditions than heterozygotes (Cohen's d=1.36; F(4,21=11.07); p=0.003), while this effect was not present in women with estradiol levels under the median concentration. the observed effect of COMT Val158Met by estradiol on overall startle response is likely to be due to a variable noradrenergic transmission depending on COMT activity in a possible interaction with estradiol.


The perceived role of Islam in immigrant Muslim medical practice within the USA: an exploratory qualitative study.
Islam and Muslims are underrepresented in the medical literature and the influence of physician's cultural beliefs and religious values upon the clinical encounter has been understudied. To elicit the perceived influence of Islam upon the practice patterns of immigrant Muslim physicians in the USA. Ten face-to-face, in-depth, semistructured interviews with Muslim physicians from various backgrounds and specialties trained outside the USA and practising within the the country. Data were analysed according to the conventions of qualitative research using a modified grounded-theory approach. There were a variety of views on the role of Islam in medical practice. Several themes emerged from our interviews: (1) a trend to view Islam as enhancing virtuous professional behaviour; (2) the perception of Islam as influencing the scope of medical practice through setting boundaries on career choices, defining acceptable medical procedures and shaping social interactions with physician peers; (3) a perceived need for Islamic religious experts within Islamic medical ethical deliberation. This is a pilot study intended to yield themes and hypotheses for further investigation and is not meant to fully characterise Muslim physicians at large. Immigrant Muslim physicians practising within the USA perceive Islam to play a variable role within their clinical practice, from influencing interpersonal relations and character development to affecting specialty choice and procedures performed. Areas of ethical challenges identified include catering to populations with lifestyles at odds with Islamic teachings, end-of-life care and maintaining a faith identity within the culture of medicine. Further study of the interplay between Islam and Muslim medical practice and the manner and degree to which Islamic values and law inform ethical decision-making is needed.


Comparative evaluation of particle agglutination test for antibody to human immunodeficiency virus.
A comparative evaluation of a new serological test for human immunodeficiency virus (HIV) was carried out. The test used the agglutination of gelatin particles coated with HIV antigen. It was found to be more sensitive than current enzyme linked immunosorbent assays (ELISAs) and more specific than the western blot test. Because of its simplicity, it promises to be of value, especially in developing countries.


Conservative management of benign oesophageal strictures.
Over a four year period, 66 patients have undergone fibreoptic endoscopy and Eder Puestow dilatation for a presumed benign oesophageal stricture. Ten patients were subsequently shown to have carcinoma of the oesophagus. There were 121 dilatations with only one perforation, which healed with conservative treatment. Twenty eight of the 56 patients with a benign stricture have required only one dilatation with relief of dysphagia during follow-up periods ranging from 11 months to 61 months (mean 29 months). In those requiring repeat dilatations, relief has been obtained for periods ranging from two weeks to 35 months (mean 6 months). Mean time to restricture in the carcinoma group was two weeks. We conclude that the Eder Puestow method is safe, well tolerated, and less than 5% will require surgery. Strictures which recur rapidly should arouse suspicion of malignancy.


"It's Okay to Say 'I Don't Know'": Medical Students Use Transformative Thinking to Cope with Ambiguity and Uncertainty.
This article was migrated. The article was marked as recommended. Uncertainty refers to the internal tension of not fully knowing or understanding a situation and is a concept that physicians must learn to deal with in order to become an effective provider. Ambiguity refers to the situation that is not fully known. Mezirow proposed that transformative learning occurs in response to a "disorienting dilemma" during which the students' frames of reference are challenged. We used his model to explain how clerkship students learn to cope with ambiguity and uncertainty. We analyzed third year medical students reflective practice essays for encounters with clinical uncertainty and ambiguity and examined how they reacted to these dilemmas. Our study is unique in its robust data set which included 273 essays.


Primary glial tumor patients treated by combining cis-platin and etoposide.
Thirty eight patients with malignant gliomas (27 GBM and 11 AA) were treated with up to 7 cycles of CDDP + VP16 every month after surgery. Chemotherapy was planned as two cycles before and 5 cycles after radiation (42 Gy) using a three times daily fractionation schedule. No severe toxicity was observed. The object of our study was to investigate the antitumor effectiveness by combining CDDP plus VP16 against primary malignant glial tumors. The time to tumor progression (TTP) and survival time (ST) of the GBM patients in the present study were 38.5 and 68.5 weeks respectively. The TTP of the AA patients was 73 weeks and the ST was not calculated as most patients are still alive. By the 18th. month after surgery, 38% of GBM and 74% of AA patients treated with (CDDP + VP16) are still alive. This study demonstrates that the combination of CDDP and VP16 is effective in patients with malignant gliomas.


Predictors of perceived barriers to physical activity in the general adult population: a cross-sectional study.
The perception of personal barriers to physical activity varies according to the sociodemographic characteristics of individuals. To determine the predictors of the perception of barriers to physical activity in the adult population. A cross-sectional study with 1066 adult women and 1036 adult men. The sociodemographic variables (age, gender, marital status, socioeconomic level, level of education), the perception of barriers that do not allow performance of physical activity (i.e. lack of time, social support, energy, motivation, skill, resources, and fear of injury during practice); and the level of physical activity through the International Physical Activity Questionnaire in its short-form version were evaluated. Individuals from low socioeconomic level (1 and 2) have higher risks of perceiving barriers such as lack of motivation [OR 1.76 (95% CI (1.4-2.1))] and lack of resources [OR 1.37 (95% CI (1.1-1.6))]; individuals with partners did not perceive the lack of social support [OR 0.29 (95% CI (0.2-0.4))] and lack of motivation [OR 0.54 (95% CI (0.4-0.7))] as barriers to physical activity. Individuals with low schooling perceived lack of social support [OR 3.81 (95% CI (3-4.7))], lack of resources [OR 2.78 (95% CI (2.2-3.3))], and fear of injury [OR 2.70 (95% CI (2.2-3.3))] as barrier to physical activity. Factors such as socioeconomic level, marital status, level of education, and self-perception of health are predictors of barriers to physical activity.


Enhancing the photocatalytic properties of PbS QD solids: the ligand exchange approach.
Surface engineering of nanomaterials is a promising tool towards the design of new materials for conversion of solar energy into chemical energy. In this work, we examine the influence of ligand exchange on the photocatalytic performance of solution-processed PbS films. We test different ligands such as oleylamine (OAm), 1,2-ethanedithiol (EDT), 3-mercaptopropionic acid (MPA) and tetrabutylammonium iodide (TBAI). The study demonstrates that PbS films capped with MPA and EDT exhibit 3.5-fold enhanced photocatalytic performance for the photodecomposition of methyl orange upon sunlight exposure. Both band energy alignment and charge carrier transport have a strong impact on the generation of reactive oxygen species (ROS), which play a key role in the photodecomposition process. Moreover, the stability and reusability of the photocatalysts are clearly improved after ligand exchange. We prove how both MPA and EDT provide much more stability to PbS QD films to operate very efficiently up to 8 cycles of photocatalysis. As observed in XPS, the oxidation of PbS is prevented after ligand exchange. We demonstrate how surface chemistry engineering of solution-processed QD films can open a new approach towards the design of highly efficient and stable visible-light-driven photocatalysts, which paves the way to low cost and large area fabrication of high-performance photocatalytic devices.


Carbon dioxide monitoring and evidence-based practice - now you see it, now you don't.
Carbon dioxide has been monitored in the body using a variety of technologies with a multitude of applications. The monitoring of this common physiologic variable in medicine is an illustrative example of the different levels of evidence that are required before any new health technology should establish itself in clinical practice. End-tidal capnography and sublingual capnometry are two examples of carbon dioxide monitoring that require very different levels of evidence before being disseminated widely. The former deserves its status as a basic standard based on observational data. The latter should be considered investigational until prospective controlled data supporting its use become available. Other applications of carbon dioxide monitoring are also discussed.


Revenge versus rapport: Interrogation, terrorism, and torture.
This review begins with the historical context of harsh interrogation methods that have been used repeatedly since the Second World War. This is despite the legal, ethical and moral sanctions against them and the lack of evidence for their efficacy. Revenge-motivated interrogations (Carlsmith & Sood, 2009) regularly occur in high conflict, high uncertainty situations and where there is dehumanization of the enemy. These methods are diametrically opposed to the humanization process required for adopting rapport-based methods-for which there is an increasing corpus of studies evidencing their efficacy. We review this emerging field of study and show how rapport-based methods rely on building alliances and involve a specific set of interpersonal skills on the part of the interrogator. We conclude with 2 key propositions: (a) for psychologists to firmly maintain the Hippocratic Oath of "first do no harm," irrespective of perceived threat and uncertainty, and (b) for wider recognition of the empirical evidence that rapport-based approaches work and revenge tactics do not. Proposition (a) is directly in line with fundamental ethical principles of practice for anyone in a caring profession. Proposition (b) is based on the requirement for psychology to protect and promote human welfare and to base conclusions on objective evidence. (PsycINFO Database Record


Development of an enzyme-linked immuno-sorbent assay (ELISA) method for carbofuran residues.
The haptens 4-[[(2,3-dihydro-2,2-dimethyl-7-benzofuranyloxy)carbonyl]-amino]butanoic acid (BFNB) and 6-[((2,3-dihydro-2,2-dimethyl-7-benzofuranyloxy)-carbonylamino]hexanoic acid (BFNH) were synthesized and then used to develop a rapid,specific and sensitive ELISA method to determine residues of the pesticide carbofuran in a variety of matrices. A hybridoma cell line (5D3) producing anti-carbofuran monoclonal antibodies (MAbs) was also established. Based on the MAbs in combination with the heterologous hapten BFNH coupled to either horseradish peroxidase (HRP) or ovalbumin(OVA), four ELISAs (formats I-IV) for the quantification of carbofuran were developed and compared. Among them, the optimized format II (the conjugate-coated direct competitive ELISA) showed the best characteristics, with an IC50 value of 18.49 ng/mL, a limit of detection of 0.11 ng/mL and the shortest assay time (1 h). This ELISA method was then applied to the determinations of carbofuran in environmental water, soil and food samples. The relative standard deviations (R.S.D.s) ranged from 1.8% to 21.3% and the mean recoveries were 104.6%, 108.3%, 106.3% and 100.1% for water, soil, lettuce and cabbage, respectively. Thus, the ELISA method of format II exhibited the potential to develop commercial ELISA kits for a rapid detection of carbofuran for human health and environmental safety.


A high resolution map of a cyanobacterial transcriptome.
Previous molecular and mechanistic studies have identified several principles of prokaryotic transcription, but less is known about the global transcriptional architecture of bacterial genomes. Here we perform a comprehensive study of a cyanobacterial transcriptome, that of Synechococcus elongatus PCC 7942, generated by combining three high-resolution data sets: RNA sequencing, tiling expression microarrays, and RNA polymerase chromatin immunoprecipitation sequencing. We report absolute transcript levels, operon identification, and high-resolution mapping of 5' and 3' ends of transcripts. We identify several interesting features at promoters, within transcripts and in terminators relating to transcription initiation, elongation, and termination. Furthermore, we identify many putative non-coding transcripts. We provide a global analysis of a cyanobacterial transcriptome. Our results uncover insights that reinforce and extend the current views of bacterial transcription.


Qi-Dong-Huo-Xue-Yin balances the immune microenvironment to protect against LPS induced acute lung injury.
COVID-19 induces acute lung injury (ALI)/acute respiratory distress syndrome (ARDS) and leads to severe immunological changes that threatens the lives of COVID-19 victims. Studies have shown that both the regulatory T cells and macrophages were deranged in COVID-19-induced ALI. Herbal drugs have long been utilized to adjust the immune microenvironment in ALI. However, the underlying mechanisms of herbal drug mediated ALI protection are largely unknown. This study aims to understand the cellular mechanism of a traditional Chinese medicine, Qi-Dong-Huo-Xue-Yin (QD), in protecting against LPS induced acute lung injury in mouse models. Our data showed that QD intrinsically promotes Foxp3 transcription via promoting acetylation of the Foxp3 promoter in CD4+ T cells and consequently facilitates CD4+CD25+Foxp3+ Tregs development. Extrinsically, QD stabilized β-catenin in macrophages to expedite CD4+CD25+Foxp3+ Tregs development and modulated peripheral blood cytokines. Taken together, our results illustrate that QD promotes CD4+CD25+Foxp3+ Tregs development via intrinsic and extrinsic pathways and balanced cytokines within the lungs to protect against LPS induced ALI. This study suggests a potential application of QD in ALI related diseases.


Controlled differentiation of human bone marrow stromal cells using magnetic nanoparticle technology.
Targeting and differentiating stem cells at sites of injury and repair is an exciting and promising area for disease treatment and reparative medicine. We have investigated remote magnetic field activation of magnetic nanoparticle-tagged mechanosensitive receptors on the cell membrane of human bone marrow stromal cells (HBMSCs) for use in osteoprogenitor cell delivery systems and activation of differentiation in vitro and in vivo toward an osteochondral lineage. HBMSC-labeled with magnetic beads coated with antibodies or peptides to the transmembrane ion channel stretch activated potassium channel (TREK-1) or arginine–glycine–aspartic acid were cultured in monolayer or encapsulated into polysaccharide alginate/chitosan microcapsules. Upregulation in gene expression was measured in magnetic particle-labeled HBMSCs in response to TREK-1 activation over a short period (7 days) with an increase in mRNA levels of Sox9, core binding factor alpha1 (Cbfa1), and osteopontin. Magnetic particle-labeled HBMSCs encapsulated into alginate chitosan capsules were exposed to magnetic forces both in vitro and in vivo intermittently for 21 days. After 21 days the encapsulated, magnetic particle-labeled HBMSCs in vivo were viable as evidenced by extensive cell tracker green fluorescence. The mechanical stimulation of HBMSCs labeled with TREK-1 magnetic nanoparticle receptors enhanced expression of type-1 collagen in vitro with increases in proteoglycan matrix, core binding factor alpha1 (Cbfa1) and collagen synthesis, and extracellular matrix production and elevated the expression of type-1 and type-2 collagen in vivo. Additionally, the magnetically remote stimulation of HBMSCs labeled with magnetic nanoparticle arginine–glycine–aspartic acid considerably enhanced proteoglycan and collagen synthesis and extracellular matrix production and elevated the expression of type-1 and type-2 collagen in vivo and in vitro. Osteogenic mechanosensitive receptor manipulation by magnetic nanotechnology can induce the differentiation of osteoprogenitor cell populations toward an osteogenic lineage. These cell manipulation strategies offer tremendous therapeutic opportunities in soft and hard tissue repair.


Population structure of humpback whales in the western and central South Pacific Ocean as determined by vocal exchange among populations.
For cetaceans, population structure is traditionally determined by molecular genetics or photographically identified individuals. Acoustic data, however, has provided information on movement and population structure with less effort and cost than traditional methods in an array of taxa. Male humpback whales (Megaptera novaeangliae) produce a continually evolving vocal sexual display, or song, that is similar among all males in a population. The rapid cultural transmission (the transfer of information or behavior between conspecifics through social learning) of different versions of this display between distinct but interconnected populations in the western and central South Pacific region presents a unique way to investigate population structure based on the movement dynamics of a song (acoustic) display. Using 11 years of data, we investigated an acoustically based population structure for the region by comparing stereotyped song sequences among populations and years. We used the Levenshtein distance technique to group previously defined populations into (vocally based) clusters based on the overall similarity of their song display in space and time. We identified the following distinct vocal clusters: western cluster, 1 population off eastern Australia; central cluster, populations around New Caledonia, Tonga, and American Samoa; and eastern region, either a single cluster or 2 clusters, one around the Cook Islands and the other off French Polynesia. These results are consistent with the hypothesis that each breeding aggregation represents a distinct population (each occupied a single, terminal node) in a metapopulation, similar to the current understanding of population structure based on genetic and photo-identification studies. However, the central vocal cluster had higher levels of song-sharing among populations than the other clusters, indicating that levels of vocal connectivity varied within the region. Our results demonstrate the utility and value of using culturally transmitted vocal patterns as a way of defining connectivity to infer population structure. We suggest vocal patterns be incorporated by the International Whaling Commission in conjunction with traditional methods in the assessment of structure.


Proteasome inhibitors synergize with tumor necrosis factor-related apoptosis-induced ligand to induce anaplastic thyroid carcinoma cell death.
Anaplastic thyroid carcinoma (ATC) is one of the most aggressive types of cancer characterized by complete refractoriness to multimodal treatment approaches. Therapeutic strategies based on the simultaneous use of proteasome inhibitors and death receptor ligands have been shown to induce apoptosis in several tumor types but have not yet been explored in ATC. The aim of this study was to investigate the ability of the proteasome inhibitor Bortezomib to induce apoptosis in ATC cell lines. Bortezomib was used as a single agent or in combination with TNF-related apoptosis-induced ligand (TRAIL), a member of the TNF family that selectively induces tumor cell apoptosis. The molecular effects of Bortezomib were investigated by analyzing the expression of key regulators of cell cycle and apoptosis and the activation of different apoptotic pathways. Bortezomib induced apoptosis in ATC cells at doses achieved in the clinical setting, differently from conventional chemotherapeutic agents. Simultaneous treatment with low doses of Bortezomib and TRAIL had a synergistic effect in inducing massive ATC cell apoptosis. Bortezomib increased the expression of cytotoxic TRAIL receptors, p21 (WAF/CIP1) and proapoptotic second mitochondria-derived activator of caspases/direct inhibitor of apoptosis binding protein with low pI, and reduced the expression of antiapoptotic mediators such as cellular Fas-associated death domain-like IL-1beta converting enzyme inhibitory protein, Bcl-2, Bcl-X(L), and inhibitor of apoptosis-1, thus resulting in cell death induction through the mitochondrial apoptotic pathway. The combination of proteasome inhibitors and TRAIL synergizes to induce the destruction of chemoresistant neoplastic thyrocytes and could represent a promising therapeutic strategy for the treatment of anaplastic thyroid carcinoma.


[Dynamics of subjective perception of in-group interaction during long-term isolation and confinement].
In experiments HUBES and ECOPSY-95 small groups of test-subjects under the conditions of long-term isolation and confinement were noted to split into two fairly stable parts each consisting of two crew members and an "outsider". Strain in the interaction between the "outsider" and the crew tended to grow in acuity as was evidenced by rise in the criteria describing behavior of a small group, and relationship. In both experiments the background for the conflict-threatening strain appeared to be a disintegrated ego-image in both of the "outsiders". Generally, infantilism of ego-image was in hand with hand with low self-assessment. Development by the subjects of ineffective patterns of the attitude system which we consider to be "escape back to the past" and "disintegration" of ego-image overlapped with the most psychologically challenging periods in the experiments, i.e. the start and the end of isolation and confinement, and off-nominal situations.


What do tests do for doctors? A qualitative study of blood testing in UK primary care.
Rates of blood testing are rising with significant geographical variability. Most research into diagnostic testing focuses on the role of tests in diagnostic decision-making. The aim of this study was to explore the non-medical motives for blood testing by considering what tests do for doctors, through qualitative interviews with general practitioners (GPs). We undertook 23 in-depth semi-structured interviews with UK GPs. Reasons for performing recent inflammatory marker blood tests were explored by reviewing GPs pathology inboxes to ground discussions in real-life clinical practice. Interviews were transcribed verbatim and analysed using a grounded theory approach. Blood tests offer doctors a tool to manage uncertainty; within a context of increased litigation, risk aversion and reduced continuity of care. Tests can also be offered as a 'gift' for patients, a way to be seen to be 'doing something'; in the social context of time pressures and perceived patient pressures. There was a tension however. On the one hand, doctors talked about using tests for reassurance and as a 'gift' offering 'truth'. Yet paradoxically, they also discussed the challenges of uncertainty and anxiety from inconclusive test results. Our study emphasises that defining 'unnecessary' blood testing may not be as simple as determining medical criteria for testing; psychosocial reasons may be equally valid and interlinked. Further research is needed to help GPs manage uncertainty within the context of a risk averse society, and to explore the congruence and dissonance between doctors' and patients' perceptions of testing.


Combined pollution characteristics and ecological risks of multi-pollutants in Poyang Lake.
Poyang Lake, the largest freshwater lake in China, faced severe ecological degradation in the past decade. Combined pollution of multi-pollutants may be one of the contributing factors. However, the characteristics of combined pollution and the ecological risks are still not clear. In this study, we used Polar Organic Chemical Integrative Sampler (POCIS), In Situ Bioassay Passive Sampling Device (ISBPSD) and conventional sampling methods, to study the toxic pollutants levels and the combined biological toxicity effects. The results showed that high levels of organochlorine pesticides (OCPs, averaged 162 ng/g) and polycyclic musk (PCM, averaged 53.6 ng/g) residues, as well as some metals such as nickel (Ni), lead (Pb) concentrations exceeded the relevant standard level in the sediment. The risk of combined pollution in the water was relatively low, but high risk was found in the sediments. According to the ISBPSD studies, the survival rates of species in the water and sediments were only 10.0-45.0% and 1.67-11.7% respectively, which was much lower than that reported in other typical basins of China. OCPs, PCMs, and certain metals such as Pb and Ni may be the key toxic pollutants causing biological toxicity effects in Poyang Lake.


The stem species of our species: a place for the archaic human cranium from Ceprano, Italy.
One of the present challenges in the study of human evolution is to recognize the hominin taxon that was ancestral to Homo sapiens. Some researchers regard H. heidelbergensis as the stem species involved in the evolutionary divergence leading to the emergence of H. sapiens in Africa, and to the evolution of the Neandertals in Europe. Nevertheless, the diagnosis and hypodigm of H. heidelbergensis still remain to be clarified. Here we evaluate the morphology of the incomplete cranium (calvarium) known as Ceprano whose age has been recently revised to the mid of the Middle Pleistocene, so as to test whether this specimen may be included in H. heidelbergensis. The analyses were performed according to a phenetic routine including geometric morphometrics and the evaluation of diagnostic discrete traits. The results strongly support the uniqueness of H. heidelbergensis on a wide geographical horizon, including both Eurasia and Africa. In this framework, the Ceprano calvarium--with its peculiar combination of archaic and derived traits--may represent, better than other penecontemporaneous specimens, an appropriate ancestral stock of this species, preceding the appearance of regional autapomorphic features.


Acquired resistance to endocrine treatments is associated with tumor-specific molecular changes in patient-derived luminal breast cancer xenografts.
Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC. Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays. HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival. PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314-25. ©2014 AACR.


Cholinergic partition cells and lamina x neurons induce a muscarinic-dependent short-term potentiation of commissural glutamatergic inputs in lumbar motoneurons.
Acetylcholine and the activation of muscarinic receptors influence the activity of neural networks generating locomotor behavior in the mammalian spinal cord. Using electrical stimulations of the ventral commissure, we show that commissural muscarinic (CM) depolarizations could be induced in lumbar motoneurons. We provide a detailed electrophysiological characterization of the muscarinic receptors and the membrane conductance involved in these responses. Activation of the CM terminals, originating from lamina X neurons and partition cells, induced a pathway-specific short-term potentiation (STP) of commissural glutamatergic inputs in motoneurons. This STP is occluded in the presence of the muscarinic antagonist atropine. During fictive locomotion, the activation of the commissural pathways transiently enhanced the motor output in a muscarinic-dependent manner. This study describes for the first time a novel regulatory mechanism of synaptic strength in spinal locomotor networks. Such cellular mechanisms would endow the locomotor central pattern generators with adaptive processes needed to generate appropriate synaptic inputs to motoneurons during different motor tasks.


C19 and C21 5 beta/5 alpha metabolite ratios in subjects treated with the 5 alpha-reductase inhibitor finasteride: comparison of male pseudohermaphrodites with inherited 5 alpha-reductase deficiency.
Male subjects administered the 5 alpha-reductase inhibitor finasteride were studied to determine its effect on C19 and C21 5 alpha-metabolism. Plasma testosterone (T) and 5 alpha-dihydrotestosterone (DHT) were measured and T/DHT ratios determined at doses of 0.2-80 mg. Urinary etiocholanolone (5 beta)/androsterone (5 alpha) ratios and 5 beta/5 alpha metabolite ratios of cortisol, 11 beta-hydroxyandrostenedione, and corticosterone were also measured. The steroid profile was compared to male pseudohermaphrodites with inherited 5 alpha-reductase deficiency who have a global defect in C19 and C21 5 alpha-metabolism. The mean plasma DHT levels were decreased at all doses, resulting in elevated T/DHT ratios. The mean urinary etiocholanolone/androsterone, 11 beta-hydroxyetiocholanolone/11 beta-hydroxyandrosterone, tetrahydrocortisol/allotetrahydrocortisol, and tetrahydrocorticosterone/allotetrahydrocorticosterone ratios were elevated compared to pretreatment levels and placebo control values. The mean ratios appeared to be dose dependent for plasma T/DHT, urinary etiocholanolone/androsterone tetrahydrocorticosterone/allotetrahydrocorticosterone ratios. The mean 11 beta-hydroxyetiocholanolone-hydroxyandrosterone ratio was maximally elevated at the lowest doses. The results indicate that finasteride has a broad steroid spectrum inhibiting C19 and C21 5 alpha-steroid metabolism and affecting hepatic and peripheral 5 alpha-metabolism. These results suggest that a single gene codes for a single 5 alpha-reductase enzyme with affinity for multiple steroid substrates. The steroid profile is strikingly similar to that of male pseudohermaphrodites with inherited 5 alpha-reductase deficiency.


Effects of hyperthyroidism on vascular contractile and relaxation responses.
Previous research has shown that skeletal muscle blood flow, at rest and during muscular contractions, is elevated in the hyperthyroid state. We hypothesized that reduced vascular contractile and enhanced endothelium-dependent relaxation responses contribute to these observations. To test these hypotheses, male rats were administered triiodothyronine (Hyper, n = 27; 300 micrograms/kg) for 6-12 wk. Compared with euthyroid control rats (Eut, n = 27), Hyper exhibited left ventricular hypertrophy (Eut, 2.01 +/- 0.04 mg/g body wt; Hyper, 2.70 +/- 0.06; P < 0.0005) and greater oxidative enzyme activity in several skeletal muscles (all P < 0.0005). Vascular rings, 2-3 mm in axial length, were prepared from abdominal aortas, and responses to vasoactive agents were determined in vitro. Compared with Eut, vascular rings with intact endothelium from Hyper exhibited reductions in contractile responses to norepinephrine (NE) across a range of NE concentrations (P < 0.05). Maximal tension developed in response to NE was reduced approximately 30% in hyperthyroidism (Eut, 3.8 +/- 0.2 g; Hyper, 2.6 +/- 0.4; P < 0.01). Contractile responses to NE were not different between Eut and Hyper in rings denuded of endothelium. Maximal vasorelaxation responses to acetylcholine (ACh), after precontraction with NE (10(-7) M), were enhanced in the hyperthyroid state (Eut, 65.1 +/- 4.8%; Hyper, 84.0 +/- 7.1; P < 0.05). Enhanced vasorelaxation to ACh was also observed when precontraction was induced by prostaglandin F2 alpha. These findings indicate that vascular contractile and relaxation responses are altered in male hyperthyroid rats.


Routes and doses of lignocaine hydrochloride for analgesia of the velvet antler of stags.
To evaluate the effectiveness of various routes of administration and doses of local anaesthetic to provide analgesia of the velvet antler of young stags. In study 1, in which an electrical stimulus was used, 64 l-year-old male red and red X wapiti deer with velvet antler lo-30 cm long, were randomly allocated to one of ten treatments with four treatments/animal, and 23 or 24 antlers/treatment. Treatments delivered included three control groups, three local anaesthetic (2% lignocaine HCL) doses delivered by ring block (5, 10 or 15 ml per pedicle), and a high or low regional block with or without an auriculopalpebral nerve block (5 ml per site). An electrical stimulus was applied before and 1,2,4 and 8 minutes after local anaesthetic treatments and to controls, at an increasing voltage until a response was observed. The voltage and animal responses were recorded. In Study 2 the same seven local anaesthetic treatments (16-I 8 antlers/treatment) were evaluated using 58 of the stags from Study 1 when antlers were ready for removal, but a saw cut was used as the test stimulus. A test cut was applied to the antler I,2 and 4 minutes after application of local anaesthetic. If no response was observed, the antler was removed at that time. In Study 1, major dose and treatment effects were significantly different (p < 0.05) with the outcome variable being whether or not the deer responded. No stags given the high dose ring block responded to electrical stimulation 1 minute after treatment, one responded at 2 minutes, and none responded at 4 or 8 minutes. At least one animal responded after all other treatments at all time intervals. More deer responded after the low regional block than the high regional block, and there was a lower response rate when the auriculopalpebral nerves were anaesthetised. In Study 2, no deer responded 2 minutes after the medium dose ring block treatment. Three of 18 stags receiving the high dose ring block still responded after 2 minutes, and one responded after 4 minutes. Responses occurred to all other treatments at each time, with some deer requiring further administration of local anaesthetic before antler removal, even with the four minute waiting period. Ring blocks produced more consistent analgesia of the velvet antler than regional nerve blocks. The high dose ring block produced analgesia faster and more effectively than lower doses, and the regional nerve blocks were more effective when the auriculopalpebral nerve was blocked.


Molecular analysis of hemolytic and phospholipase C activities of Pseudomonas cepacia.
By using a gene-specific fragment from the hemolytic phospholipase C (PLC) gene of Pseudomonas aeruginosa as a probe and data from Southern hybridizations under reduced stringency conditions, we cloned a 4.2-kb restriction fragment from a beta-hemolytic Pseudomonas cepacia strain which expressed hemolytic and PLC activities in Escherichia coli under the control of the lac promoter. It was found, by using a T7 phage promoter-directed expression system, that this DNA fragment carries at least two genes. One gene which shares significant DNA homology with both PLC genes from P. aeruginosa encodes a 72-kDa protein, while the other gene encodes a 22-kDa protein. When both genes on the 4.2-kb fragment were expressed from the T7 promoter in the same cell, hemolytic and PLC activities could be detected in the cell lysate. In contrast, when each individual gene was expressed in different cells or when lysates containing the translated products of each separate gene were mixed, neither hemolytic activity nor PLC activity could be detected. Clinical and environmental isolates of P. cepacia were examined for beta-hemolytic activity, PLC activity, sphingomyelinase activity, and reactivity in Southern hybridizations with a probe from P. cepacia which is specific for the larger gene which encodes the 72-kDa protein. There were considerable differences in the ability of the different strains to express hemolytic and PLC activities, and the results of Southern DNA-DNA hybridizations of the genomic DNAs of these strains revealed considerable differences in the probe-reactive fragments between high- and medium-stringency conditions as well as remarkable variation in size and number of probe-reactive fragments among different strains. Analysis of the genomic DNAs from hemolytic and nonhemolytic variants of an individual strain (PC-69) by agarose gel electrophoresis. Southern hybridization, and transverse alternating pulsed field gel electrophoresis suggests that the conversion of the hemolytic phenotype to the nonhemolytic phenotype is associated with either the loss of a large plasmid (greater than 200 kb) or a large deletion of the chromosome of P. cepacia PC-69.


The effects of halogen elements on the opening of an icosahedral B12 framework.
The fully halogenated or hydrogenated B12X122- (X = H, F, Cl, Br and I) clusters are confirmed to be icosahedral. On the other hand, the bare B12 cluster is shown to have a planar structure. A previous study showed that a transformation from an icosahedron to a plane happens when 5 to 7 iodine atoms are remained [P. Farràs et al., Chem. - Eur. J. 18, 13208-13212 (2012)]. Later, the transition was confirmed to be seven iodine atoms based on an infrared spectroscopy study [M. R. Fagiania et al., Chem. Phys. Lett. 625, 48-52 (2015)]. In this study, we investigated the effects of different halogen atoms on the opening of the B12 icosahedral cage by means of density functional theory calculations. We found that the halogen elements do not have significant effects on the geometries of the clusters. The computed infrared (IR) spectra show similar representative peaks for all halogen doped clusters. Interestingly, we found a blue-shift in the IR spectra with the increase in the mass of the halogen atoms. Further, we compared the Gibbs free energies at different temperatures for different halogen atoms. The results show that the Gibbs free energy differences between open and close structures of B12X7- become larger when heavier halogen atoms are presented. This interesting finding was subsequently investigated by the energy decomposition analysis.


Representational dynamics of object vision: the first 1000 ms.
Human object recognition is remarkably efficient. In recent years, significant advancements have been made in our understanding of how the brain represents visual objects and organizes them into categories. Recent studies using pattern analyses methods have characterized a representational space of objects in human and primate inferior temporal cortex in which object exemplars are discriminable and cluster according to category (e.g., faces and bodies). In the present study we examined how category structure in object representations emerges in the first 1000 ms of visual processing. In the study, participants viewed 24 object exemplars with a planned categorical structure comprised of four levels ranging from highly specific (individual exemplars) to highly abstract (animate vs. inanimate), while their brain activity was recorded with magnetoencephalography (MEG). We used a sliding time window decoding approach to decode the exemplar and the exemplar's category that participants were viewing on a moment-to-moment basis. We found exemplar and category membership could be decoded from the neuromagnetic recordings shortly after stimulus onset (<100 ms) with peak decodability following thereafter. Latencies for peak decodability varied systematically with the level of category abstraction with more abstract categories emerging later, indicating that the brain hierarchically constructs category representations. In addition, we examined the stationarity of patterns of activity in the brain that encode object category information and show these patterns vary over time, suggesting the brain might use flexible time varying codes to represent visual object categories.


Aberrant interleukin-1 signalling does not increase susceptibility of mice to NOD2-dependent uveitis.
NOD2 is the genetic cause of Blau syndrome, an autoinflammatory disease that manifests as coincident uveitis and arthritis. Since dysregulation of IL-1 signalling is considered a pathogenic mechanism in a number of related autoinflammatory conditions, we examined the extent to which unimpeded interleukin (IL)-1 signalling influences NOD2-dependent inflammation of the eye versus the joint. Mice deficient for IL-1R antagonist (IL-1Ra) were administered the NOD2 agonist muramyl dipeptide (MDP) by systemic (intraperitoneal) or local (intraocular and/or intra-articular) injections. NOD2-deficient mice received an intraocular injection of recombinant IL-1β. Uveitis was evaluated by intravital videomicroscopy and histopathology, and arthritis was assessed by near-infrared imaging and histopathology. Ocular levels of IL-1α, IL-1β and IL-1Ra were quantified by enzyme-linked immunosorbent assay. IL-1Ra deficiency did not render mice more responsive to systemic exposure of MDP. Despite the increased production of IL-1R agonists IL-1α and IL-1β in response to intraocular injection of MDP, deficiency in IL-1Ra did not predispose mice to MDP-triggered uveitis, albeit intravascular cell rolling and adherence were exacerbated. NOD2 expression was dispensable for the potential of IL-1 to elicit uveitis. However, we find that IL-1Ra does play an important protective role in arthritis induced locally by MDP injection in the joint. Our findings highlight the complexity of NOD2 activation and IL-1 signalling effects that can be compounded by local environmental factors of the target organ. These observations may impact how we understand the molecular mechanisms by which NOD2 influences inflammation of the eye versus joint, and consequently, treatment options for uveitis versus arthritis.


Hospitalization for peptic ulcer and bleeding in users of selective COX-2 inhibitors and nonselective NSAIDs with special reference to celecoxib.
To assess the relative incidence of peptic ulcer bleeding and perforation (PUBP) in users of selective cyclooxygenase-2 (COX-2) inhibitors and nonselective nonsteroidal anti-inflammatory drugs (NSAIDs). This was a retrospective case-control study based on insurance claims, with chart review to confirm cases. The base population consisted of 2.2 million adult users of celecoxib, diclofenac, ibuprofen, naproxen, rofecoxib, or valdecoxib who were covered by commercial health insurance in the United States from 1999-2003. For 790 persons hospitalized for PUBP and 7887 controls, most recent NSAID/COX-2 use and a variety of medical and pharmacy risk factors were ascertained from the insurance files and analyzed by conditional logistic regression. The main outcome measure was the odds ratio (OR) associated with use of each drug by comparison to naproxen, and in successive intervals after last dispensing. Hospitalization for PUBP was highest from the date of NSAID/COX-2 dispensing through the end of an exposure period that corresponded to the days supply; the rate dropped steadily thereafter. The covariate-adjusted ORs by comparison to naproxen were: ibuprofen 0.86 (95% confidence interval (CI) 0.68, 1.09), rofecoxib 0.79 (0.62, 1.02), diclofenac 0.66 (0.47, 0.94), valdecoxib 0.50 (0.26, 0.97), and celecoxib 0.45 (0.35, 0.58). The nonselective NSAIDs had an OR for PUBP of 1.51 (1.26, 1.98) compared to the selective COX-2 inhibitors. Nonselective NSAIDs convey half again as much risk of hospitalization for PUBP as do COX-2 inhibitors. Celecoxib users had about half the hospitalization rate of users of naproxen.


Binding Thermodynamics of Fourth-Generation EGFR Inhibitors Revealed by Absolute Binding Free Energy Calculations.
The overexpression or mutation of the kinase domain of the epidermal growth factor receptor (EGFR) is strongly associated with non-small-cell lung cancer (NSCLC). EGFR tyrosine kinase inhibitors (TKIs) have proven to be effective in treating NSCLC patients. However, EGFR mutations can result in drug resistance. To elucidate the mechanisms underlying this resistance and inform future drug development, we examined the binding affinities of BLU-945, a recently reported fourth-generation TKI, to wild-type EGFR (EGFRWT) and its double-mutant (L858R/T790M; EGFRDM) and triple-mutant (L858R/T790M/C797S; EGFRTM) forms. We compared the binding affinities of BLU-945, BLU-945 analogues, CH7233163 (another fourth-generation TKI), and erlotinib (a first-generation TKI) using absolute binding free energy calculations. Our findings reveal that BLU-945 and CH7233163 exhibit binding affinities to both EGFRDM and EGFRTM stronger than those of erlotinib, corroborating experimental data. We identified K745 and T854 as the key residues in the binding of fourth-generation EGFR TKIs. Electrostatic forces were the predominant driving force for the binding of fourth-generation TKIs to EGFR mutants. Furthermore, we discovered that the incorporation of piperidinol and sulfone groups in BLU-945 substantially enhanced its binding capacity to EGFR mutants. Our study offers valuable theoretical insights for optimizing fourth-generation EGFR TKIs.


Cost-effectiveness of 5-aminosalicylic acid therapy for maintenance of remission in ulcerative colitis.
Oral 5-aminosalicylic acid (5-ASA, mesalamine) is effective in inducing and maintaining remission in ulcerative colitis (UC). The relative benefits and costs of maintenance 5-ASA therapy are uncertain. Our aims were to evaluate this strategy's potential cost-effectiveness. We constructed a Markov model to compare two strategies over 2 yr: (a) no maintenance 5-ASA, with 5-ASA 4.8 g/day given for flares, (b) maintenance 5-ASA 2.4 g/day, escalated and maintained at 4.8 g/day after the first flare. In both arms, the failure to induce remission led to other treatments, as needed: prednisone, parenteral corticosteroids, cyclosporine, 6-mercaptopurine, infliximab, and colectomy. Without maintenance 5-ASA, the mean flares per person were 1.92, and the mean cost per person was $3,402. With maintenance 5-ASA providing a relative risk of flare of 0.7 at 5-ASA cost of $198/month, flares per person decreased to 1.38 at a cost of $8,810/flare prevented. Maintenance 5-ASA increased discounted quality-adjusted life-years per person (QALYs per person) from 1.75 to 1.77 at a discounted cost of $224,000/QALY gained. The results were most sensitive to the flare risk reduction and cost of 5-ASA, the utilities of being in remission without or with 5-ASA, and the colectomy rates. At $15/month (the cost of sulfasalazine), maintenance 5-ASA cost $640/flare prevented and $16,300/QALY gained. Maintenance 5-ASA therapy decreases UC flares, but its cost may be substantial, depending on society's willingness to pay. If sulfasalazine can be tolerated and yields comparable benefits, sulfasalazine maintenance therapy is likely to be cost-effective. The cost per QALY gained by 5-ASA maintenance is highly dependent on the quality of life while taking versus not taking maintenance 5-ASA, highlighting the importance of patients' preferences.